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(Circulation. 1997;95:2286-2292.)
© 1997 American Heart Association, Inc.

Articles

Differential Effects of Captopril and Nitrates on Muscle Sympathetic Nerve Activity in Volunteers

Georg Noll, MD; René R. Wenzel, MD; Stefano de Marchi, MD; Sidney Shaw, PhD; Thomas F. Lüscher, MD

the Cardiology and Cardiovascular Research Division (G.N., R.R.W., S. de M., T.F.L.) and Division of Hypertension (S.S.), University Hospital, Inselspital, Bern, Switzerland.

Correspondence to Georg Noll, MD, Cardiology, University Hospital, CH-8091, Zürich, Switzerland. E-mail 101372.3337{at}compuserve.com

	Abstract

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Background The sympathetic nervous system (SNS) is an important regulator of cardiovascular function. Activation of SNS plays an important role in the pathophysiology and the prognosis of cardiovascular diseases such as heart failure, acute coronary syndromes, arrhythmia, and possibly hypertension. Vasodilators such as adenosine and sodium nitroprusside are known to activate SNS via baroreflex mechanisms. Because vasodilators are widely used in the treatment of patients with cardiovascular diseases, the aim of the present study was to assess the influence of clinically used dosages of isosorbide dinitrate and captopril on sympathetic nerve activity at rest and during stimulatory maneuvers.

Methods and Results Twenty-eight healthy volunteers were included in this double-blind placebo-controlled study, and muscle sympathetic nerve activity (MSA; with microelectrodes in the peroneal nerve), blood pressure, heart rate, and neurohumoral parameters were measured before and 90 minutes after the oral administration of 40 mg isosorbide dinitrate or 6.25 mg captopril. Furthermore, a 3-minute mental stress test and a cold pressor test were performed before and 90 minutes after drug administration. Resting MSA did not change after captopril and decreased compared with placebo (P<.05 versus placebo), whereas isosorbide dinitrate led to a marked increase in MSA (P<.05). Systolic blood pressure was reduced by isosorbide dinitrate (P<.05), whereas captopril decreased diastolic blood pressure (P<.05). The increases in MSA, blood pressure, and heart rate during mental stress were comparable before and after drug administration regardless of the medication. During cold pressor test, MSA and systolic and diastolic blood pressures increased to the same degree independent of treatment, but after isosorbide dinitrate, the increase in MSA seemed to be less pronounced. Heart rate did not change during cold stimulation. Plasma renin activity increased after captopril and isosorbide dinitrate (P<.05), whereas placebo had no effect. Endothelin-1 increased after placebo and isosorbide dinitrate (P<.05) but not after captopril.

Conclusions Thus, captopril suppressed MSA despite lowering of diastolic blood pressure but allowed normal adaptation of the SNS during mental or physical stress. In contrast, the nitrate strongly activated the SNS under baseline conditions. These findings demonstrate that vasodilators differentially interact with the SNS, which could be of importance in therapeutic strategies for the treatment of patients with cardiovascular diseases.

Key Words: nervous system, autonomic • angiotensin • drugs • nitroglycerin

	Introduction

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The sympathetic nervous system (SNS) is a most important regulator of the cardiovascular system in health and disease. Its resting activity seems to be determined by genetic factors.¹ Several feedback mechanisms have been shown to be involved in the regulation of sympathetic activity, such as baroreceptors, mechanoreceptors, and chemoreceptors.^{2 3 4}

There are different methods of measuring activity of the SNS. Microneurography allows the continuous assessment of sympathetic activity in peripheral nerves. Because activation of SNS is of importance in the pathophysiology and the prognosis of cardiovascular diseases, such as acute coronary syndromes, arrhythmias, congestive heart failure, and possibly essential hypertension, the effect of therapy and its interaction with the SNS could be essential. Certain cardiovascular hormones and drugs have been shown to influence muscle sympathetic nerve activity (MSA) either directly or via reflex mechanisms.^{5 6 7 8 9} Early studies revealed that intravenous sodium nitroprusside increases MSA.^{4 7 10} This increase has been attributed to baroreceptor-mediated feedback mechanisms. Whether the oral administration of clinically used nitrates also stimulates MSA remains unknown. Baroreceptor-mediated mechanisms have also been implicated in the phenylephrine-induced decrease in MSA.¹¹ Recently, it was demonstrated that intravenous infusion of angiotensin II is associated with a relative activation of MSA.¹²

In several cardiovascular diseases, the renin-angiotensin system is activated and together with the activation of the SNS determines prognosis.¹³ ACE inhibitors that primarily affect the peripheral circulation and its regulatory mechanisms not only improve symptoms in patients with left ventricular dysfunction and/or congestive heart failure but also reduce acute coronary events and death.^{14 15 16 17 18 19} Plasma norepinephrine decreases during therapy with ACE inhibitors.^{20 21} However, whether this is due to a direct influence on the SNS and/or to beneficial hemodynamic effects is not yet clear. Conflicting results have been reported on the influence of ACE inhibitors on sympathetically mediated reflex changes using exercise and cold pressor testing.^{22 23 24 25 26}

Endothelin-1 is a recently discovered potent vasoconstrictor peptide that is released from endothelial cells.^{27 28} Several factors have been shown to increase endothelin-1 synthesis, such as angiotensin II, transforming growth factor-ß₁, and thrombin.^{28 29 30} Endothelin-1 plasma levels are increased in heart failure,^{31 32 33} myocardial infarction,^{34 35} arteriosclerosis,³⁶ and possibly hypertension.³⁷ In myocardial infarction, an increased endothelin plasma level is a marker of a poor prognosis.³⁸ There are several lines of evidence that an interaction exists between the SNS and plasma levels of endothelin-1. In disease states with activation of the SNS, such as congestive heart failure and myocardial infarction, marked increases in endothelin plasma levels have been described.^{31 32 34 38 39} Furthermore, during cold pressor testing, a parallel increase in MSA and plasma endothelin-1 has been demonstrated.^{40 41}

We therefore investigated with healthy volunteers in a placebo-controlled, randomized study the effects of a single dose of the ACE inhibitor captopril and the nitrovasodilator isosorbide dinitrate on MSA at rest and during mental stress and cold pressor testing and on endothelin-1 plasma levels.

	Methods

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Study Population
Thirty-three healthy volunteers (28 men and 5 women) were initially included in the study. Five have been excluded due to the loss of the nerve signal during the protocol. Thus, 28 subjects (26 men and 2 women) were used for the analysis. Their mean±SEM age was 24±1 years, weight was 80±1 kg, and height was 181±1 cm. The subjects were free of any cardiovascular or other diseases as determined on the basis of the medical history and a physical examination performed before the study. Informed consent was obtained from all subjects. The study was approved by the ethical committee of the University Hospital (Inselspital) (Bern, Switzerland). Three treatment groups in whom MSA was measured were investigated in a double-blind fashion: (1) a group of volunteers who received 6.25 mg captopril PO (n=9), (2) a group who received 40 mg isosorbide dinitrate PO (n=9), and (3) a group who were treated with placebo (n=10).

Experimental Protocol
All subjects were studied under the same conditions, ie, in the morning (9:00 AM) after a light breakfast. After micturition to avoid any increase in sympathetic nerve activity through bladder distention,⁴² subjects were asked to resume the supine position. The left or right leg was fixed by a vacuum cushion, and ECG leads, blood pressure cuff, and respiration strain gauge were attached. A catheter (Venflon, Ohmeda) was inserted into a cubital vein. Thirty minutes after puncture of the vein, baseline recordings, including blood samplings, were performed. When changes in the electrode position occurred, the experiment was stopped, and the results were discarded.

All subjects underwent a mental stress test and a cold pressor test (see below) with and without drug administration. The mental stress test was performed by unexpectedly asking the subject to perform mental arithmetic consisting of continued subtractions for 3 minutes.⁴³ After 15 minutes of resting, a cold pressor test was performed by immersing one of the subject's hands up to the wrist in ice water for 2 minutes.⁴¹ Subjects were asked to avoid isometric contraction, Valsalva maneuver, or holding expiration during the cold pressor test. After the tests, a single dose of the drugs (6.25 mg captopril, 40 mg isosorbide dinitrate, or placebo) was administered orally to the subjects. When estimated peak drug plasma levels were achieved, ie, 90 minutes after ingestion, the tests were repeated. If muscle contractions occurred during the maneuvers, causing EMG artifacts in the neurogram, the results of the test were discarded.

Blood samples for endothelin-1 and plasma renin activity were obtained before and 90 minutes after drug administration. Blood samples for plasma levels of captopril and isosorbide dinitrate were obtained at baseline as well as 105 minutes after drug ingestion.

Microneurography
Multifiber recordings of MSA were obtained from the peroneal nerve posterior to the fibular head with tungsten microelectrodes (200-µm shaft diameter, 1 to 5 µm, uninsulated tip; Medical Instruments, University of Iowa). A reference electrode was inserted subcutaneously 1 to 2 cm from the recording electrode. Electrodes were connected to a preamplifier (gain, 1.000) and amplifier (variable gain, 10 to 50). Neural activity was fed through a band-pass filter (bandwidth, 700 to 2000 Hz) and then a resistance-capacitance integrating network (time constant, 0.1 second) to obtain a mean voltage neurogram. The signal was displayed on an oscilloscope and registered on a thermocoupled printer at a paper speed of 5 mm/s (Graphtec Inc). In addition, the nonintegrated signal was recorded on the printer; this helped to better identify artifacts. Furthermore, the signal was amplified and connected to a loudspeaker to further identify the characteristic signal and exclude artifacts.

Three criteria for acceptance of MSA recording were required: (1) electrical stimulation (0.1 to 1.0 V, 0.2 millisecond, 1 Hz) through the electrode in the peroneal nerve elicited involuntary muscle contractions in the peroneal nerve but no paresthesia; (2) tapping or stretching the innervated muscle region elicited afferent mechanoreceptor discharges, whereas stroking of the skin did not; and (3) the neurogram revealed spontaneous, intermittent, pulse-synchronous sympathetic bursts that increased during apnea.^{6 44 45 46} Neurograms with cutaneous sympathetic activity or mixed cutaneous and muscle sympathetic nerve activity were not accepted. This was assessed by the response to arousal stimuli that elicited single reflex bursts of cutaneous, but not muscle, sympathetic activity. If there was any evidence of a dislocation of the electrode position, the experiment was excluded from the study.

ECG and Blood Pressure
An ECG was recorded simultaneously on the printer throughout the experiment. Blood pressure was assessed noninvasively through oscillometric occlusion (Dinamap, Critikon Inc).

Drugs
Captopril, isosorbide dinitrate, and identical placebo tablets were provided by Schwarz Pharma (Liestal, Switzerland).

Plasma Levels of Drugs and Hormones
Endothelin-1 levels and plasma renin activity were measured with radioimmunoassay.^{47 48} Plasma levels of isosorbide dinitrate, isosorbide-2-nitrate, and isosorbide-5-nitrate levels were measured with gas chromatography (Department of Bioanalytics, Schwarz Pharma, Monheim, Germany).⁴⁹ Captopril plasma levels were determined by high-performance liquid chromatography (Department of Bioanalytics, Schwarz Pharma, Monheim, Germany).⁵⁰

Data and Statistical Analysis
The values were registered and analyzed using StatView 4.1 (ABACUS Inc). Data are given as mean±SEM. The significance of differences between the groups, of the changes after drug ingestion, and of the changes during stress tests within the groups were calculated with the use of ANOVA. When a significant F ratio was observed, Fisher's protected least significant differences test was used to locate significant differences. To analyze the drug effects on endothelin plasma levels, a paired Student's t test was also used. A value of P<.05 was considered statistically significant.

	Results

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Baseline Conditions
MSA
Baseline values for resting MSA were comparable in all three groups (Table 1). At 90 minutes after drug administration, MSA increased significantly after placebo administration. The increase was more pronounced after isosorbide dinitrate administration, but MSA decreased slightly after captopril administration (Figs 1 and 2, Table 1; P<.05 versus placebo).

View this table: [in this window] [in a new window]   Table 1.

View larger version (28K): [in this window] [in a new window]   Figure 1. Representative recordings of muscle sympathetic activity (MSA), blood pressure values, and heart rate of three different subjects receiving either placebo (top), captopril (middle), or isosorbide dinitrate (ISDN; bottom) before (left) and after (right) drug administration. No change in MSA occurred in the captopril-treated subject, whereas a slight increase after placebo and a more pronounced one was seen in the ISDN-treated subject.

View larger version (27K): [in this window] [in a new window]   Figure 2. Change in resting muscle sympathetic activity (MSA) 90 minutes after oral administration of placebo, 6.25 mg captopril, and 40 mg isosorbide dinitrate (ISDN). A significant increase in MSA was observed in subjects who received placebo. The increase of MSA after ISDN was more pronounced compared with placebo. In subjects treated with captopril, MSA did not change. *P<.05 vs placebo, #P<.05 vs isosorbide dinitrate.

Blood Pressure and Heart Rate
Resting systolic blood pressure did not change after captopril and placebo. In the group receiving isosorbide dinitrate, systolic blood pressure was slightly lower at baseline and further decreased after drug administration (Table 1; P<.05 versus before drug administration). Initial diastolic blood pressure was comparable in all three groups. After placebo administration, a slight increase in diastolic blood pressure was measured, whereas it remained unchanged after isosorbide dinitrate and decreased after captopril (Table 1; P<.05).

Resting heart rate was comparable in all three groups, and drug administration did not influence heart rate (Table 1).

Hormones
The increase in plasma renin activity was more pronounced after captopril administration than after isosorbide dinitrate (Table 1; P<.05), whereas placebo had no effect on plasma renin activity.

With the use of ANOVA, the increase in endothelin-1 was not significantly different in the three treatment groups. With the use of paired Student's t tests, however, a significant increase was seen after placebo and isosorbide dinitrate administration (isosorbide dinitrate, P=.0015; placebo, P=.0055; Table 1), whereas after captopril, endothelin-1 did not increase significantly (P=.12).

Drug Levels
At 105 minutes after drug administration, plasma levels for captopril were 78±18 ng/mL. Plasma levels of isosorbide-5-nitrate (205±43 ng/mL), isosorbide-2-nitrate (52±8 ng/mL), and isosorbide dinitrate (18±3 ng/mL) were measured.

Mental Stress
MSA
During 3 minutes of mental arithmetic, MSA increased to a similar degree in all groups before and after drug administration (Table 2).

View this table: [in this window] [in a new window]   Table 2.

Blood Pressure and Heart Rate
Mental stress led to an increase in systolic and diastolic blood pressure, which was comparable in all groups before and after drug administration (Table 2; P<.05). After drug administration, resting systolic blood pressure was lower in the isosorbide dinitrate group compared with the placebo group, whereas diastolic blood pressure was lower in the captopril-treated group compared with the placebo group.

Heart rate increased during mental stress in all treatment groups to a comparable degree regardless of whether the subject had received the drugs (Table 2).

Cold Pressor Test
MSA
The cold pressor test was performed for 2 minutes and was accompanied by a comparable increase in MSA in all groups. The increase of MSA was not affected by the drug (Table 3).

View this table: [in this window] [in a new window]   Table 3.

Blood Pressure and Heart Rate
Systolic and diastolic blood pressure increased during cold pressor test in all groups regardless of treatment. Resting systolic blood pressure after isosorbide dinitrate was lower compared with the groups receiving placebo or captopril (Table 3). Cold pressor test did not influence heart rate in all groups regardless of drug administration (Table 3).

	Discussion

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The results of the present study demonstrate for the first time through direct measurement of sympathetic nerve activity with microneurography that nitrates and captopril differentially regulate sympathetic outflow in humans. Although the ACE inhibitor inhibited MSA, isosorbide dinitrate was associated with a marked stimulation of the system.

The efficacy of cardiovascular drugs primarily depends on their action in the blood vessel wall and myocardium. However, some of the beneficial effects of the drugs in the circulation, ie, vasodilation and stimulation of myocardial contractility, may be overcome at least in part by their effects on neurohumoral regulators. Indeed, reflex tachycardia is a known unwanted effect that is associated with several vasodilators. The fact that plasma catecholamines, an indirect measure of the activity of the SNS, are predictors of survival in patients with cardiovascular diseases suggests that these effects may be important not only for symptoms but also for the natural history of cardiovascular disease.

In this study, MSA was measured under baseline conditions as well as during different stimulatory maneuvers. Under baseline conditions, MSA increased slightly in the placebo group, possibly due to the slight discomfort associated with a prolonged immobilization in a supine position. In subjects treated with captopril, MSA did not change after the ACE inhibitor, whereas MSA increased after placebo and was markedly stimulated after isosorbide dinitrate administration. Because diastolic blood pressure slightly decreased in subjects treated with the ACE inhibitor, this strongly suggests a direct inhibition of sympathetic outflow by the drug. Indeed, diastolic blood pressure rather than systolic blood pressure seems to be important for baroreceptor-mediated activation of the SNS.⁴ Thus, in the presence of a decrease in diastolic blood pressure, one would expect an increase in sympathetic nerve activity. Experimentally, angiotensin II stimulates sympathetic outflow by activating specific binding sites in the brainstem.^{51 52 53} Furthermore, MSA is increased in patients with renovascular hypertension and consecutively increased angiotensin II in plasma as well as in healthy subjects during infusion of angiotensin II.^{12 54} Therefore, inhibition of the formation of angiotensin II by an ACE inhibitor such as captopril might offset this direct stimulatory effect of angiotensin II and in turn lower baseline sympathetic nerve activity. Our data are in line with the observation by Niederberger et al⁵⁵ in a rat model of renal hypertension, in which lisinopril as well as losartan had no influence on splanchnic sympathetic nerve activity despite a reduction in blood pressure, whereas sodium nitroprusside led to an increase in sympathetic nerve activity.

In contrast to captopril, the nitrovasodilator isosorbide dinitrate was associated with a marked increase in sympathetic nerve activity, confirming earlier studies of the intravenous administration of other nitrovasodilators.^{4 7 10} Our results are of particular interest because the dose used in our study was relatively small to match the expected hemodynamic effects of captopril. Thus, isosorbide dinitrate had little effect on blood pressure and did not influence heart rate but still led to a marked activation of MSA. The mechanisms for the isosorbide dinitrate–induced increase in MSA include (1) an arterial baroreceptor-mediated mechanism caused by a decrease in pulse pressure and (2) activation of low-pressure receptors caused by a possible decrease in central venous pressure.

In addition to resting MSA, sympathetic activity was measured during stimulation. The response to mental stress, which leads to a relatively weak stimulation of the SNS, was comparable in all groups. These results indicate that the response to a relatively weak stimulus of sympathetic activation is not affected by either isosorbide dinitrate or captopril. During the cold pressor test, which represents the strongest known stimulus for sympathetic activation,⁴¹ MSA again increased similarly in subjects regardless of treatment, suggesting that the ACE inhibitor and isosorbide dinitrate do allow the SNS to appropriately adapt during situations of increased stress. Other studies have addressed the question whether ACE inhibition affects plasma norepinephrine levels and/or the response to stressful stimuli in patients with congestive heart failure or essential hypertension. In the CONSENSUS trial, chronic enalapril treatment reduced resting plasma catecholamines.²⁰ This could be due to direct inhibition of the SNS or to an improvement in the cardiac function. Similarly, McGrath and Arnolda²⁵ found after 4 weeks of enalapril treatment a blunted increase in norepinephrine plasma concentrations during exercise in heart failure patients. Fahy et al,²³ however, did not find any changes in plasma levels of norepinephrine at rest or during physical exercise after 12 weeks of therapy with lisinopril in patients with mild heart failure. In hypertension, conflicting results have also been reported. In one study, blood pressure and norepinephrine at rest as well as the increase in these parameters during a cold pressor test were blunted by a low dose of enalapril,²⁶ whereas in another study with fosinopril, no influence was seen of the ACE inhibitor on norepinephrine at rest and during stimulation.²² Similar to our study, blood pressure was reduced, but the response to cold stimulation was unaffected. Also, in hypertensive patients with an activated renin-angiotensin system caused by a low sodium diet, benazepril reduced resting plasma norepinephrine levels.²⁴ Overall, therefore, most studies in patients with hypertension and congestive heart failure seem to find an interaction between the SNS and renin-angiotensin system. Most negative results can be accounted for by small patient numbers, noncomparable stress tests, and the use of the not very sensitive catecholamine determination in peripheral venous blood to quantify the activity of the SNS. Our results with direct measurement of sympathetic nerve activity indicate an inhibitory effect of ACE inhibitors on electrical activity in peripheral sympathetic nerves under baseline but not stimulated conditions. However, a small effect of the drugs under stimulated conditions cannot be excluded with certainty due to the relatively small numbers of subjects.

Plasma levels of endothelin-1, a potent vasoconstrictor peptide, increased in parallel to MSA. Indeed, in subjects who received placebo or isosorbide dinitrate, a significant increase in plasma endothelin-1 levels was recorded, whereas no significant change occurred after captopril administration. These findings could be related to the fact that endothelin synthesis is stimulated by angiotensin II as has been demonstrated in cultured endothelial cells.^{28 30} Furthermore, endothelin plasma levels increase in parallel with an activation of the SNS, as seen during the cold pressor test.⁴⁰ Thus, it is likely that inhibition of angiotensin II formation in the captopril-treated subjects as well as the marked stimulation of the muscle SNS after isosorbide dinitrate administration resulted in the observed changes in endothelin plasma levels seen in our study. As expected, the increase in plasma renin activity in subjects treated with captopril was more pronounced compared with the other groups, an effect that can be accounted for by the pharmacological property of the drug. In the nitrate-treated group, the increase in plasma renin activity could be due to the blood pressure–lowering effect with consecutive activation of the renin-angiotensin system either directly or via ß-receptors due to increased activity in renal sympathetic nerves.

Despite the fact that the results of this short-term study were obtained in healthy volunteers with a low drive of the renin-angiotensin system, they may have some importance for the treatment strategies in patients with cardiovascular diseases, in whom sympathetic activation is an important determinant of prognosis.⁵⁶ Our results cannot be directly extrapolated to the effects of chronic therapy in patients with activation of neurohumoral systems, in whom higher doses of ACE inhibitors are used. We chose such a small dose to avoid substantial blood pressure reduction with consecutive baroreceptor-mediated activation of the SNS and to match the expected hemodynamic effects of isosorbide dinitrate. Nevertheless, the influence of medication on SNS may be relevant for the treatment of such patients because chronic ß-blockade improves survival in patients with heart failure.⁵⁷ The inhibitory effect of captopril on sympathetic nerve activity, in addition to the improvement of hemodynamics, may importantly contribute to the known beneficial effects of ACE inhibitors on survival in patients after acute myocardial infarction and those with heart failure.^{15 16 17} In contrast, the use of nitrates as monotherapy does not influence survival after myocardial infarction,^{18 19} whereas a combination of nitrates with lisinopril enhanced the beneficial effect of the ACE inhibitor.¹⁸ Based on these results, the selection of vasodilator drugs for the treatment of coronary syndromes, hypertension, and congestive heart failure should also take into consideration their effects on the SNS.

	Acknowledgments

 
This study was supported by grants from the Swiss National Research Foundation (32-32.655.91 and 32-35.591.92 SCORE), the German Research Association (Deutsche Forschungsgemeinschaft; WE1772/1-1), the Schweizerische Herzstiftung, and the Sandoz Research Foundation and a grant-in-aid from Schwarz Pharma, Liestal, Switzerland.

Received August 5, 1996; revision received December 2, 1996; accepted December 2, 1996.

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